Greater than 50% of patients with the aggressive form of the systemic sclerosis (SSc) die or develop organ failure within 5 years, and standardized mortality rates have remained unchanged over past four decades. Skin and lung fibrosis are major causes of morbidity and mortality, and have no approved treatment. Fibrosis results from myofibroblast activation in injured microenvironments, initiated and sustained by inflammatory cells, transforming growth factor- (TGF-) and reactive oxygen species (ROS). Dissecting the intracellular signaling networks controlling the process can lead to the discovery of therapeutic targets. I showed that CDDO, a synthetic derivative of the naturally occurring oleanolic acid, inhibit myofibroblast differentiation and attenuate fibrosis in two distinct mouse models of scleroderma. Therefore CDDO and related synthetic oleananes (SOs) with drug-like properties represent a potential therapeutic approach to fibrosis. Furthermore, I recently identified a potentially critical role for Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) in regulating myofibroblast activation and development of fibrosis, and mediating anti-fibrotic effects of CDDO. My hypothesis is that second-generation SOs with excellent safety profile will demonstrate Nrf2-mediated anti-fibrotic effects in fibroblasts, and will mitigate the key pathogenetic features of SSc (immune dysregulation, oxidative stress and fibrosis) and result in reduced fibroblast activation, reversal of the myofibroblast phenotype and mitigated organ fibrosis in mouse models. Working in collaboration with Drs. Liby and Sporn (Pharmacology, Dartmouth Medical School), I will i) examine anti-fibrotic effects of two second-generation SOs with high potency to induce Nrf2 activity in vitro using explanted fibroblasts, human skin equivalents and skin organoids, and explore the mechanism of action; ii) evaluate their ability to prevent, as well as to reverse, fibrosis in the skin using complementary inflammatory and non-inflammatory mouse models of scleroderma. The proposed studies are expected to establish the role of Nrf2-mediated responses in pathogenesis, and identify novel SO compounds with potent anti-fibrotic activity. Combined with their known antioxidant and immunomodulatory effects, and superior safety profiles, SOs might be highly effective for the therapy of SSc.